The impact of epigenetic dysregulation associated with mutational crosstalk on driving early bladder cancer progression

In bladder carcinogenesis little research on the epigenetic landscapes of urothelial clonal expansions from carcinoma in situ (CIS) towards muscle invasive bladder cancers (MIBC) has been done. Therefore, we aim to decipher intra- and interpatient specific patterns of DNA methylation (DNAme) responsible for gene expression changes which are potentially causative for progression to invasive clones in tumor evolution of bladder cancer. We will use a unique resource of matched tissue samples from histologically mapped cystectomy specimens of patients, each comprising normal urothelium (NU), spatially distinct CIS lesions and MIBC. Together with project P7 data will be biostatistically analyzed allowing the inference of epigenetic events with genetics, clonality and phylogeny of the tumors in individuals as well as across patients. To specify the identified DNAme patterns in the context of clonal expansions, phylogenetic information of the mouse studies of project P2 will be implemented into the biostatistical pipeline. Following the published workflow of the Börries group project P7, a validation approach will be applied to extract a robust panel of gene candidates associated with patient survival. These studies of selected genes will involve the introduction of appropriate genetic modifications in cell culture systems followed by assays to determine cell proliferation, migration or invasion. We will provide a multi-dimensional, integrated view of the genetic and epigenetic alterations underlying the different types of tumor evolution of invasive clones.